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Q03526 (ITK_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 152. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Tyrosine-protein kinase ITK/TSK

EC=2.7.10.2
Alternative name(s):
IL-2-inducible T-cell kinase
Kinase EMT
Kinase TLK
T-cell-specific kinase
Gene names
Name:Itk
Synonyms:Emt, Tlk, Tsk
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length625 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Ref.14

Catalytic activity

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

Cofactor

Binds 1 zinc ion per subunit By similarity.

Subunit structure

Homooligomerizes; this association negatively regulates kinase activity. Interacts with PPIA/CYPA; this interaction regulates TCR signal strength via a proline-directed conformational switch in ITK. Interacts with THEMIS By similarity. Interacts with FASLG. Interacts with VAV1; this interaction is important for VAV1 localization and TCR-induced actin polarization. Ref.6 Ref.13

Subcellular location

Cytoplasm. Note: Localizes in the vicinity of cell surface receptors in the plasma membrane after receptor stimulation By similarity.

Tissue specificity

Is detected in the thymus, lymph node and very faintly in the spleen, but is not detected in the liver, lung, kidney, heart, brain, intestine or testis. Expressed in T-lymphocytes and mast cells. It may also be expressed in natural killer cells.

Developmental stage

Is present in the fetal thymus as early as day 14 of gestation. The levels are 5- to 10-fold higher in thymocytes than in peripheral T-cells, and increase in the thymus during development from neonate to adult.

Induction

Through a myriad of surface receptors including the TCR/CD3 signaling complex, coreceptors, or chemokine receptors.

Domain

The N-terminal PH domain allows ITK to be recruited to the plasma membrane by an activated PI3 kinase. This domain contains also a proline-rich region (PRR). The adjoining domain is a SH3 domain, which binds to PRR (from itself or from other proteins). Next, a SH2 domain is required for binding tyrosine-phosphorylated substrates. In the C-terminal region, the kinase domain is required for tyrosine phosphorylation By similarity.

Post-translational modification

Phosphorylated at Tyr-517 in the activation loop of the kinase domain by LCK. Subsequent autophosphorylation at Tyr-186 leads to the kinase activation. The autophosphorylated Tyr-186 lies within the substrate binding sequence of the SH3 domain By similarity.

Ubiquitinated By similarity.

Disruption phenotype

Mice display decreased mature thymocytes and elicit profound defect in CD4+ and CD8+ T-cell development. Additionally, they show a strong decrease of cytokine production in response to TCR receptor stimulation. Ref.5 Ref.11 Ref.12 Ref.14

Sequence similarities

Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily.

Contains 1 Btk-type zinc finger.

Contains 1 PH domain.

Contains 1 protein kinase domain.

Contains 1 SH2 domain.

Contains 1 SH3 domain.

Ontologies

Keywords
   Biological processAdaptive immunity
Immunity
   Cellular componentCytoplasm
   DomainSH2 domain
SH3 domain
Zinc-finger
   LigandATP-binding
Metal-binding
Nucleotide-binding
Zinc
   Molecular functionKinase
Transferase
Tyrosine-protein kinase
   PTMPhosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processNK T cell differentiation

Inferred from mutant phenotype PubMed 18292523. Source: MGI

T cell receptor signaling pathway

Inferred from mutant phenotype Ref.11. Source: UniProtKB

activation of phospholipase C activity

Inferred from mutant phenotype Ref.11. Source: UniProtKB

adaptive immune response

Inferred from mutant phenotype Ref.11. Source: UniProtKB

cytokine production

Inferred from mutant phenotype Ref.11. Source: UniProtKB

interferon-gamma production

Inferred from mutant phenotype PubMed 18292523. Source: MGI

interleukin-4 production

Inferred from mutant phenotype PubMed 18292523. Source: MGI

intracellular signal transduction

Inferred from electronic annotation. Source: InterPro

peptidyl-tyrosine phosphorylation

Inferred from sequence or structural similarity. Source: GOC

   Cellular_componentcell-cell junction

Inferred from direct assay PubMed 23793062. Source: MGI

cytosol

Traceable author statement. Source: Reactome

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

non-membrane spanning protein tyrosine kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.6. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 625625Tyrosine-protein kinase ITK/TSK
PRO_0000088107

Regions

Domain4 – 117114PH
Domain177 – 23761SH3
Domain245 – 34399SH2
Domain368 – 620253Protein kinase
Zinc finger119 – 15537Btk-type
Nucleotide binding374 – 3829ATP By similarity

Sites

Active site4871Proton acceptor By similarity
Metal binding1271Zinc By similarity
Metal binding1381Zinc By similarity
Metal binding1391Zinc By similarity
Metal binding1491Zinc By similarity
Binding site3961ATP By similarity

Amino acid modifications

Modified residue1861Phosphotyrosine; by autocatalysis By similarity
Modified residue5171Phosphotyrosine; by LCK By similarity
Modified residue5701Phosphoserine By similarity

Experimental info

Sequence conflict82 – 876Missing Ref.2
Sequence conflict82 – 876Missing Ref.3
Sequence conflict82 – 876Missing Ref.4
Sequence conflict5351F → S in L10628. Ref.3
Sequence conflict5401Y → C in L10628. Ref.3

Secondary structure

............................................. 625
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q03526 [UniParc].

Last modified February 1, 1995. Version 1.
Checksum: F7A4A18A8A1AADDC

FASTA62572,292
        10         20         30         40         50         60 
MNNFILLEEQ LIKKSQQKRR TSPSNFKVRF FVLTKASLAY FEDRHGKKRT LKGSIELSRI 

        70         80         90        100        110        120 
KCVEIVKSDI SIPCHYKYPF QTLVYLQVVH DNYLLYVFAP DCESRQRWVL TLKEETRNNN 

       130        140        150        160        170        180 
SLVSKYHPNF WMDGRWRCCS QLEKPAVGCA PYDPSKNASK KPLPPTPEDN RRSFQEPEET 

       190        200        210        220        230        240 
LVIALYDYQT NDPQELALRC DEEYYLLDSS EIHWWRVQDK NGHEGYAPSS YLVEKSPNNL 

       250        260        270        280        290        300 
ETYEWYNKSI SRDKAEKLLL DTGKEGAFMV RDSRTPGTYT VSVFTKAIIS ENPCIKHYHI 

       310        320        330        340        350        360 
KETNDSPKRY YVAEKYVFDS IPLLIQYHQY NGGGLVTRLR YPVCSWRQKA PVTAGLRYGK 

       370        380        390        400        410        420 
WVIQPSELTF VQEIGSGQFG LVHLGYWLNK DKVAIKTIQE GAMSEEDFIE EAEVMMKLSH 

       430        440        450        460        470        480 
PKLVQLYGVC LEQAPICLVF EFMEHGCLSD YLRSQRGLFA AETLLGMCLD VCEGMAYLEK 

       490        500        510        520        530        540 
ACVIHRDLAA RNCLVGENQV IKVSDFGMTR FVLDDQYTSS TGTKFPVKWA SPEVFSFSRY 

       550        560        570        580        590        600 
SSKSDVWSFG VLMWEVFSEG KIPYENRSNS EVVEDISTGF RLYKPRLASC HVYQIMNHCW 

       610        620 
KEKPEDRPPF SQLLSQLAEI AEAGL 

« Hide

References

[1]"itk, a T-cell-specific tyrosine kinase gene inducible by interleukin 2."
Siliciano J.D., Morrow T.A., Desiderio S.V.
Proc. Natl. Acad. Sci. U.S.A. 89:11194-11198(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Thymocyte.
[2]"Developmental regulation of a murine T-cell-specific tyrosine kinase gene, Tsk."
Heyeck S.D., Berg L.J.
Proc. Natl. Acad. Sci. U.S.A. 90:669-673(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Thymocyte.
[3]"Structure and expression of novel protein-tyrosine kinases, Emb and Emt, in hematopoietic cells."
Yamada N., Kawakami Y., Kimura H., Fukamachi H., Baier G., Altman A., Kato T., Inagaki Y., Kawakami T.
Biochem. Biophys. Res. Commun. 192:231-240(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: CBA/J.
Tissue: Mast cell.
[4]Ogata M., Sawada M., Fujiwara H., Hamaoka T.
Submitted (JAN-1993) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]"Altered T cell receptor signaling and disrupted T cell development in mice lacking Itk."
Liao X.C., Littman D.R.
Immunity 3:757-769(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
[6]"Themis controls thymocyte selection through regulation of T cell antigen receptor-mediated signaling."
Fu G., Vallee S., Rybakin V., McGuire M.V., Ampudia J., Brockmeyer C., Salek M., Fallen P.R., Hoerter J.A.H., Munshi A., Huang Y.H., Hu J., Fox H.S., Sauer K., Acuto O., Gascoigne N.R.J.
Nat. Immunol. 10:848-856(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH THEMIS.
[7]"Regulatory intramolecular association in a tyrosine kinase of the Tec family."
Andreotti A.H., Bunnell S.C., Feng S., Berg L.J., Schreiber S.L.
Nature 385:93-97(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 160-236.
[8]"CD28 is associated with and induces the immediate tyrosine phosphorylation and activation of the Tec family kinase ITK/EMT in the human Jurkat leukemic T-cell line."
August A., Gibson S., Kawakami Y., Kawakami T., Mills G.B., Dupont B.
Proc. Natl. Acad. Sci. U.S.A. 91:9347-9351(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION.
[9]"CD2 signaling in T cells involves tyrosine phosphorylation and activation of the Tec family kinase, EMT/ITK/TSK."
King P.D., Sadra A., Han A., Liu X.-R., Sunder-Plassmann R., Reinherz E.L., Dupont B.
Int. Immunol. 8:1707-1714(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION.
[10]"Emt/Itk associates with activated TCR complexes: role of the pleckstrin homology domain."
Ching K.A., Kawakami Y., Kawakami T., Tsoukas C.D.
J. Immunol. 163:6006-6013(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION.
[11]"Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity."
Schaeffer E.M., Debnath J., Yap G., McVicar D., Liao X.C., Littman D.R., Sher A., Varmus H.E., Lenardo M.J., Schwartzberg P.L.
Science 284:638-641(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
[12]"Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk."
Broussard C., Fleischacker C., Horai R., Chetana M., Venegas A.M., Sharp L.L., Hedrick S.M., Fowlkes B.J., Schwartzberg P.L.
Immunity 25:93-104(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
[13]"Disrupting the intermolecular self-association of Itk enhances T cell signaling."
Min L., Wu W., Joseph R.E., Fulton D.B., Berg L., Andreotti A.H.
J. Immunol. 184:4228-4235(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBUNIT.
[14]"Interleukin-2-inducible T cell kinase (Itk) network edge dependence for the maturation of iNKT cell."
Qi Q., Xia M., Bai Y., Yu S., Cantorna M., August A.
J. Biol. Chem. 286:138-146(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN INVARIANT NKT CELL MATURATION, DISRUPTION PHENOTYPE.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L00619 mRNA. Translation: AAA39337.1.
L05631 mRNA. Translation: AAA40518.1.
L10628 mRNA. No translation available.
D14042 mRNA. Translation: BAA03129.1.
CCDSCCDS70169.1.
PIRA43030.
RefSeqNP_001268894.1. NM_001281965.1.
NP_001268895.1. NM_001281966.1.
NP_001268897.1. NM_001281968.1.
NP_034713.2. NM_010583.3.
UniGeneMm.339927.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1AWJNMR-A160-236[»]
1LUINMR-A238-344[»]
1LUKNMR-A238-344[»]
1LUMNMR-A238-344[»]
1LUNNMR-A238-344[»]
2ETZNMR-A238-344[»]
2EU0NMR-A238-344[»]
2K79NMR-A177-237[»]
B238-344[»]
2K7ANMR-A177-237[»]
B238-344[»]
2RN8NMR-A177-238[»]
2RNANMR-A177-238[»]
3S9KX-ray2.35A236-344[»]
ProteinModelPortalQ03526.
SMRQ03526. Positions 5-623.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid200840. 5 interactions.
DIPDIP-29283N.
IntActQ03526. 4 interactions.
MINTMINT-84965.

PTM databases

PhosphoSiteQ03526.

Proteomic databases

PRIDEQ03526.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000109237; ENSMUSP00000104860; ENSMUSG00000020395.
GeneID16428.
KEGGmmu:16428.
UCSCuc011xtn.1. mouse.

Organism-specific databases

CTD3702.
MGIMGI:96621. Itk.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00640000091251.
HOGENOMHOG000233859.
HOVERGENHBG008761.
InParanoidQ03526.
KOK07363.
OMARRNEEYC.
PhylomeDBQ03526.
TreeFamTF351634.

Enzyme and pathway databases

BRENDA2.7.10.1. 3474.

Gene expression databases

ArrayExpressQ03526.
BgeeQ03526.
CleanExMM_ITK.
GenevestigatorQ03526.

Family and domain databases

Gene3D2.30.29.30. 1 hit.
3.30.505.10. 1 hit.
InterProIPR011009. Kinase-like_dom.
IPR011993. PH_like_dom.
IPR001849. Pleckstrin_homology.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR000980. SH2.
IPR001452. SH3_domain.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR001562. Znf_Btk_motif.
[Graphical view]
PfamPF00779. BTK. 1 hit.
PF00169. PH. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 1 hit.
PF00018. SH3_1. 1 hit.
[Graphical view]
PRINTSPR00401. SH2DOMAIN.
PR00402. TECBTKDOMAIN.
PR00109. TYRKINASE.
SMARTSM00107. BTK. 1 hit.
SM00233. PH. 1 hit.
SM00252. SH2. 1 hit.
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMSSF50044. SSF50044. 1 hit.
SSF55550. SSF55550. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEPS50003. PH_DOMAIN. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50001. SH2. 1 hit.
PS50002. SH3. 1 hit.
PS51113. ZF_BTK. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ03526.
NextBio289653.
PROQ03526.
SOURCESearch...

Entry information

Entry nameITK_MOUSE
AccessionPrimary (citable) accession number: Q03526
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: February 1, 1995
Last modified: July 9, 2014
This is version 152 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot